For years, researchers have worked to decipher the complex ecology of the human microbiome. Decades of research and multi-omics have brought us to transition from correlation and observational studies to causation on microbiome-based therapies. However, we still lack a consensus on what constitutes a “healthy” microbiome. This reflects the complexity of the system and highlights the futility of a one-size-fits-all approach, due to confounding variables like diet, geography, age, sex, and lifestyle. Instead, clinicians and researchers are beginning to adopt a more nuanced view, using the microbiome in three main ways: as a mechanism, a metric, or a modifier.
- As a mechanism, the microbiome is studied for its causal role in health and disease. While the “chicken-or-egg” dilemma remains (whether changes in the microbiome cause or simply reflect disease), emerging technologies are increasingly capable of establishing causality.
- As a metric, it offers diagnostic or prognostic value, predicting who is at risk or who might benefit from specific therapies.
- As a modifier, it becomes a tool, manipulated through diet, probiotics, or microbial transplants to restore health thanks to targeted treatments.
This conceptual framework is not theoretical. It is already reshaping approaches to cancer immunotherapy, infection control, and neonatal care. However, the field still lacks clinical guidelines, validated tools, and regulatory clarity. A recent review in Nature Medicine1 outlines the current landscape, feasibility, and outstanding gaps in microbiome research.
From concept to clinic: five cases that reflect a field in transition
Where does microbiome-based medicine stand today, and where is it headed? To illustrate these questions and reflect the subjects discussed in the publication in Nature Medicine, we present five simulated clinical cases, each featuring insights from the authors and experts Prof. Jack Gilbert, PhD, microbial ecologist from University of California San Diego, and Dr. Katrine Whiteson, PhD, from the University of California Irvine. Their perspectives reveal a field in transition, moving from research promise to real-world application.
#1 Colorectal cancer prediction using gut microbiome
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. While colonoscopies remain the gold standard for screening, interest is growing in non-invasive tools such as microbiome-based stool testing2 that could also be applied to inflammatory bowel diseases.3,4
According to Gilbert, such tools are beginning to show clinical utility, “We have identified stool biomarkers that predict CRC recurrence5 after surgery. This enables early, proactive interventions that can accelerate recovery. For instance, a two-week dietary intervention can shift the microbiome to promote better post-operative outcomes.” However, current stool tests lack the resolution of colonoscopies, particularly in detecting lesions in the upper colon. Their predictive power, while promising, remains inferior. “Patients understandably want alternatives to invasive procedures,” Whiteson added. “Stool microbiome signatures can identify some polyp types, but we need more robust data before these tests can replace standard screening tools.”
Where microbiome insights already hold clinical value is in supportive care. “Dietary fiber, for instance, can improve chemotherapy outcomes,” said Whiteson. “This advice is not yet uniformly applied in clinical settings, but the evidence is strong. I often recommend patients start simple; even adding chia seeds to their daily routine.” Gilbert shared a personal approach: “Whenever I am scheduled for surgery, I make sure to eat very healthily for two to three weeks beforehand; 30 or more plant species per week, plenty of colourful fruits and vegetables, and a reduction in alcohol, refined sugars, and processed foods. I also spend more time in nature to prepare my immune system and microbiome for optimal recovery.”
#2 Personalised nutrition interventions based on the microbiome to improve metabolic health
With cardiometabolic diseases on the rise globally, the idea of tailoring diet to the gut microbiome is gaining momentum. But how close are we to realizing this vision?
“Personalized nutrition is coming,” said Gilbert. “Artificial intelligence (AI)-powered biomarker discovery, mucosal sampling, and engineered biosensors are driving rapid progress. We are seeing the emergence of ‘digital twin’ models that predict individual responses to different diets.” However, until these tools mature, the most effective advice remains behavioral: “Eat a diverse, plant-rich diet and spend time outdoors. These habits consistently support a healthy gut microbiome.”
Whiteson cautioned against over-reliance on direct-to-consumer microbiome testing services, “There is currently no strong evidence that these tests can accurately predict individual metabolic risk or optimize diet in a clinically meaningful way. We need longitudinal datasets that track diet and stool over time to uncover useful patterns”. In the meantime, public education is essential. “At UC Irvine, we run a ‘teaching kitchen’ where chefs prepare meals while we explain their microbiome impact,” said Whiteson. “It is practical and empowering. Hospitals should also lead by example and improve the nutritional quality of their own meals.”
#3 Can probiotics and vaginal microbiota transfers boost vaginal health?
Microbiome based therapy are employed to maintain a healthy vaginal microbiome, protecting against sexually transmitted infections and urinary tract infections. A balanced microbial environment supports mucosal immunity and plays a critical role in fertility and pregnancy outcomes. However, disruptions to this ecosystem can lead to persistent conditions such as bacterial vaginosis.
Recurrent bacterial vaginosis remains difficult to treat, often relapsing after antibiotic therapy. “There is real therapeutic potential in targeting the vaginal microbiome,” noted Whiteson. “But unlike fecal microbiota transfers (FMTs), which are regulated and partly reimbursed, vaginal microbiome transplants remain experimental and carry risk.” A lack of donor biobanks, safety protocols, and regulatory oversight continues to delay implementation. “Many commercial vaginal probiotics contain strains that do not colonize effectively,” Whiteson added. “There is no vaginal equivalent to gut-proven strains like Lacticaseibacillus rhamnosus GG and Saccharomyces cerevisiae CNCM I-745, among others.” Until clinical evidence and infrastructure improve, dietary strategies remain a low-risk option: “I often recommend diversifying the intake of fermented food as a familiar and affordable probiotic source,” said Whiteson.
#4 Probiotics in preterm infants
The early-life microbiome, particularly rich in Bifidobacterium, plays a crucial role in shaping immunity and reducing the risk of disease later in life. Current microbiome-based interventions aim to mitigate the effects of C-section births and promote beneficial colonization through breast milk or formulas enriched with components that mimic its properties, such as galacto-oligosaccharides, secretory IgA, and probiotics.
In preterm infants, early microbial colonization is critical. Necrotizing enterocolitis (NEC) and sepsis are highly prevalent among very preterm infants, and modulating the microbiome could reduce this risk. “Clinical trials such as EVIVO have shown that specific probiotic strains can reduce the incidence of NEC,” explained Whiteson. “But these products are not yet standard due to regulatory hesitations—especially after isolated cases of sepsis.” She believes timing and precision are key: “We may not need prolonged courses; just a single, well-timed dose paired with breast milk or human milk oligosaccharides may suffice. It is about encouraging colonization without increasing the risk of sepsis.”
#5 Advocating for phage therapy, probiotics, or fecal microbiota to tackle antibiotic-resistant infections
As antibiotic resistance escalates, alternatives like phage therapy and FMT are gaining traction. “For recurrent Clostridioides difficile, FMT remains our best option,” said Gilbert. “FDA-approved products like broad consortium of live microbes are available, but other applications remain experimental”. Currently, trials are exploring other uses of FMT on non-communicable diseases such as graft-versus-host disease or non-alcoholic fatty liver disease.
Whiteson is cautiously optimistic about phage therapy: “Recent FDA approvals (for conditions like sinusitis) are encouraging. But we still need clinical-grade phage libraries and clearer regulatory frameworks.” Currently, phage cocktails are being tested on targeting Pseudomonas aeruginosa involved in cystic fibrosis.
Ultimately, both experts agree that prevention begins with microbiome resilience. “Feed it with fiber. Create an environment where beneficial microbes can thrive,” said Whiteson.
Conclusion
Microbiome-based care is moving from concept to clinic, but progress is slow. As Gilbert notes, “Even when efficacy is clear, product development is long and costly. Oral microbiome therapeutics decade-plus journey and nine-figure price tag are not outliers.” Safety concerns, such as donor screening or phage resistance, also demand stricter risk-benefit frameworks. To move forward, we need sustained investment in clinical studies and real-world testing, alongside deeper engagement with clinicians, hospital leaders, and public health professionals, to ensure these tools can be used safely and effectively in practice. “I think we’ll need public-private partnerships and innovative funding models to support the development of more acute interventions as for instance, the antibiotic subscription schemes, promoting access to essential treatments while encouraging innovation. Similar models could help support the development of microbiome-based therapeutic” said Whiteson.
References:
- Gilbert, J. A., Azad, M. B., Bäckhed, F., Blaser, M. J., Byndloss, M., Chiu, C. Y., Chu, H., Dugas, L. R., Elinav, E., Gibbons, S. M., Gilbert, K. E., Henn, M. R., Ishaq, S. L., Ley, R. E., Lynch, S. V., Segal, E., Spector, T. D., Strandwitz, P., Suez, J., Tropini, C., Whiteson, K., & Knight, R. (2025). Clinical translation of microbiome research. Nature Medicine, 31, 1099–1113. https://doi.org/10.1038/s41591-025-03615-9
- World Health Organization. (2024, July 11). Colorectal cancer. WHO. Retrieved June 16, 2025, from https://www.who.int/news-room/fact-sheets/detail/colorectal-cancer
- Oliver, L., Camps, B., Julià-Bergkvist, D., Amoedo, J., Ramió-Pujol, S., Malagón, M., Bahí, A., Torres, P., Domènech, E., Guardiola, J., Serra‑Pagès, M., Garcia‑Gil, J., & Aldeguer, X. (2023). Definition of a microbial signature as a predictor of endoscopic post‑surgical recurrence in patients with Crohn’s disease. Frontiers in Molecular Medicine, 3, Article 1046414. https://doi.org/10.3389/fmmed.2023.1046414
- Busquets, D., Oliver, L., Amoedo, J., Ramió‑Pujol, S., Malagón, M., Serrano, M., Bahí, A., Capdevila, M., Lluansí, A., Torrealba, L., Peries, L., Chavero, R., Gilabert, P., Sàbat, M., Guardiola, J., Serra‑Pagès, M., Garcia‑Gil, J., & Aldeguer, X. (2021). RAID Prediction: Pilot Study of Fecal Microbial Signature With Capacity to Predict Response to Anti‑TNF Treatment. Inflammatory Bowel Diseases, 27(Suppl 2), S63– https://doi.org/10.1093/ibd/izab273
- Yu, L., Zhao, G., Wang, L., Zhou, X., Sun, J., Li, X., Zhu, Y., He, Y., Kofonikolas, K., Bogaert, D., Dunlop, M., Zhu, Y., Theodoratou, E., & Li, X. (2022). A systematic review of microbial markers for risk prediction of colorectal neoplasia. British Journal of Cancer, 126(9), 1318–1328. https://doi.org/10.1038/s41416-022-01740-7
- Mullard, A. (2023). FDA approves second microbiome‑based C. difficile therapy. Nature Reviews Drug Discovery, 22, 436. https://doi.org/10.1038/d41573-023-00081-1